Dataset Information

Elongator complex deficiency in sonic hedgehog medulloblastoma

ABSTRACT: Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHH subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Medulloblastoma Cell

SUBMITTER: Valentin SABATET

LAB HEAD: Damarys Loew

PROVIDER: PXD016832 | Pride | 2020-04-23

REPOSITORIES: Pride

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Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

Waszak Sebastian M SM Robinson Giles W GW Gudenas Brian L BL Smith Kyle S KS Forget Antoine A Kojic Marija M Garcia-Lopez Jesus J Hadley Jennifer J Hamilton Kayla V KV Indersie Emilie E Buchhalter Ivo I Kerssemakers Jules J Jäger Natalie N Sharma Tanvi T Rausch Tobias T Kool Marcel M Sturm Dominik D Jones David T W DTW Vasilyeva Aksana A Tatevossian Ruth G RG Neale Geoffrey G Lombard Bérangère B Loew Damarys D Nakitandwe Joy J Rusch Michael M Bowers Daniel C DC Bendel Anne A Partap Sonia S Chintagumpala Murali M Crawford John J Gottardo Nicholas G NG Smith Amy A Dufour Christelle C Rutkowski Stefan S Eggen Tone T Wesenberg Finn F Kjaerheim Kristina K Feychting Maria M Lannering Birgitta B Schüz Joachim J Johansen Christoffer C Andersen Tina V TV Röösli Martin M Kuehni Claudia E CE Grotzer Michael M Remke Marc M Puget Stéphanie S Pajtler Kristian W KW Milde Till T Witt Olaf O Ryzhova Marina M Korshunov Andrey A Orr Brent A BA Ellison David W DW Brugieres Laurence L Lichter Peter P Nichols Kim E KE Gajjar Amar A Wainwright Brandon J BJ Ayrault Olivier O Korbel Jan O JO Northcott Paul A PA Pfister Stefan M SM

Nature 20200401 7803

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children<sup>1,2</sup>, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the maligna ...[more]

PMID: 32296180

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Project description:Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHHa subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

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